The invention relates to certain novel compounds, to pharmaceutical compositions containing such compounds, to a process for the preparation of such compounds and to the use of such compounds as active therapeutic agents.
Anti-arrhythmic agents are classified according to their electrophysiological effects on the cardiac cell Vaugham-Williams, 1970, 1989): class I agents block the fast sodium current, class II agents are beta-adrenergic blockers, class III agents block potassium currents, class IV agents block the calcium current, and class V agents are specific sinus node inhibitors.
A majority of ventricular and atrial arrhythmias are related to reentrant circuit. The prolongation of myocardial refractoriness within or surrounding such a reentrant circuit is a potential mechanism for the management of cardiac arrhythmias.
Because class III antiarrhytmic agents block cardiac potassium currents, they prolong the repolarisation process and increase refractoriness. Consequently class III agents represent the most specific class to treat reentrant arrhythmias.
However, due to their mechanism of action, i.e. a concentration dependent increase in the cardiac action potential duration, higher doses of class III antiarrhythmic agents may trigger arrhythmias. Such arrhythmias, called Torsade de Pointe represent the main adverse effect for all pure class III compounds currently in development.
European Patent Application, Publication Number 0 245 997 discloses certain aminoethylsulphoanilides which are stated to have pure class III antiarrhythmic properties.
It has now been discovered that certain novel substituted 4-nitrobenzamide derivatives induce a self-limiting increase of the cardiac action potential duration, related to a dual blockade of cardiac potassium and calcium channels. Consequently, they are considered to be useful anti-arrhythmic agents having an improved pharmacological profile over pure class III anti-arrhythmic agents, in particular they are considered to show a low proarrhythmic potential and readily restore the contractile function of the ischaemic myocardium. They are considered to be particularly useful for the treatment of atrial or ventricular cardiac arrhythmias.
Accordingly, the invention relates to a compound of formula (I): 
or a salt thereof, or a solvate thereof, wherein
Ar represents substituted or unsubstituted aryl, wherein the optional substituents are selected from alkyl, hydroxy or alkoxy or, if attached to adjacent carbon atoms any two substituents together with the carbon atoms to which they are attached may form a fused heterocyclic ring of five to six atoms wherein one, two or three of the said atoms are oxygen or nitrogen;
A represents a C1-4 n-alkylene group wherein each carbon is optionally substituted by 1 or 2 C1-6 alkyl groups;
R1 represents hydrogen, alkyl, alkenyl or cycloalkyl; one or two of the group of R2, R3 and R4 represents nitro the remaining members of the group of R2, R3 and R4 represent hydrogen;
X represents a xe2x80x94COxe2x80x94NHxe2x80x94 moiety; and
Z represents C2-4 n-alkylene group wherein each carbon is optionally substituted by 1 or 2 C1-6 alkyl groups.
Suitable substituents for Ar are 1, or favourably, 2 alkoxy groups, especially methoxy groups, the substituents favourably being attached at the 3- and 4-positions relative to the point of attachment of Ar to variable A.
Preferably, Ar represents 3,4-dimethoxyphenyl
Suitably, A represents an unsubstituted C1-4 n-alkylene group.
Preferably, A represents xe2x80x94CH2xe2x80x94CH2.
When R1 is alkyl it is preferably C2-6 alkyl such as C2- alkyl, C3 alkyl, C4 alkyl, C5 alkyl or C6 alkyl.
In one aspect, R1 is alkylene or cycloalkyl.
Preferably, R1 is hydrogen.
Suitably, any one of R2, R3 and R4 represents nitro and the remaining members of the group of R2, R3 and R4 represent hydrogen.
Preferably, R2 represents 4-nitro.
Preferably, R3 and R4 each represents hydrogen.
Suitably, Z represents an unsubstituted C2-4 n-alkylene group.
Suitably, Z represents CH2CH2CH2.
A particularly preferred compound of formula is N-[3-[[2-(3,4 -dimethoxyphenyl)ethyl]amino]propyl]-4-nitro benzamide or a salt thereof, such as a hydrochloride salt, or a solvate thereof.
As used herein unless otherewise stated, the term xe2x80x9calkylxe2x80x9d includes straight or branched chain alkyl groups having from 1 to 12, favourably 1 to 6 carbon atoms and shall include such alkyl groups when forming part of other groups such as alkoxy or arylalkyl groups.
As used herein, the term xe2x80x9calkylenexe2x80x9d includes straight or branched chain alkylene groups having from 2 to 12, favourably 2 to 6 carbon atoms.
As used herein, the term xe2x80x9ccycloalkylxe2x80x9d includes C3-8 cycloalkyl groups, favourably C5-6 carbon groups.
As used herein, unless otherwise stated, the term xe2x80x9carylxe2x80x9d includes phenyl and naphthyl, preferably phenyl.
As used herein, unless otherwise stated, xe2x80x9chalogenxe2x80x9d includes fluorine, chlorine or bromine.
As used herein, the term xe2x80x9ccardiac arrhythmiaxe2x80x9d relates to any variation from the normal rhythm of heart beat, including, without limitation, sinus arrhythmia, premature heartbeat, heartblock, fibrillation, flutter, tachycardia, paroxysmal tachycardia and premature ventricular contractions.
The compounds of formula (I) may possess a chiral carbon atom (for example when Z represents a branched alkylene group and may therefore exist in more than one stereoisomeric form. The invention extends to any of the stereoisomeric forms, including enantiomers of the compounds of formula (I) and to mixtures thereof, including racemates. The different stereoisomeric forms may be separated or resolved one from the other by conventional methods or any given isomer may be obtained by conventional stereospecific or asymmetric syntheses.
The pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts with pharmaceutically acceptable mineral acids such as hydrochloric, hydrobromic, boric, phosphoric, sulphuric and pharmaceutically acceptable organic acids such as acetic, tartaric, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, xcex1-keto-glutaric, xcex1-glycerophosphoric, and glucose-1-phosphoric acids. Preferably the acid addition salt is a hydrochloride.
Pharmaceutically acceptable salts include pharmaceutically acceptable N-oxides, and the invention extends to these.
The compounds of the formula (I) and their salts may also form solvates, especially pharmaceutically acceptable solvates, such as hydrates, and the invention extends to these, and especially to the pharmaceutically acceptable solvates.
The salts and/or solvates of the compounds of the formula (I) which are not pharmaceutically acceptable may be useful as intermediates in the preparation of pharmaceutically acceptable salts of compounds of formula (I) or the compounds of the formula (I) themselves, and as such form an aspect of the present invention.
A compound of formula (I), or a salt thereof, or a solvate thereof, may be prepared by reacting a compound of formula (II): 
wherein A, Ar, R1 and Z are as defined in relation to formula (I), with a compound of formula (III): 
wherein R2, R3 and R4 are as defined in relation to formula (I) and L1 represents a leaving group; and thereafter, if required, carrying out one or more of the following optional steps:
(i) converting a compound of formula (I) into a further compound of formula (I);
(ii) preparing a salt of the compound of formula (I) and/or a pharmaceutically acceptable solvate thereof.
Compounds of formula (III) are known, commercially available compounds.
The reaction between the compounds of formulae (II) and (III) may be carried out in any suitable inert solvent, such as dichloromethane, in the presence of a base, usually an organic base, for example triethylamine, at a temperature which provides a suitable rate of formation of the required product, generally at a low to ambient temperature, preferably ambient
A preferred leaving group L1 is a halogen atom, such as a chlorine atom.
The compounds of formula (II) are known compounds and may be prepared by the method described in Offenlegungsschrift 2345423.
The compounds of formula (II) may also be prepared by reducing a compound of formula (IV): 
wherein A, Ar and R1 arm as defined in relation to the compound of formula (I) and Z1 represents C1-3 n-alkylene group wherein each carbon is optionally substituted by a C1-6 alkyl group.
The reduction of the compounds of formulae (IV) may be carried out using conventional reducing agents and conditions, for example by using a metal hydride reducing agent, such as lithium aluminium hydride, in an aprotic solvent, such as tetrahydrofuran or diethyl ether or mixtures thereof, at a temperature which provides a suitable rate of formation of the required product, generally at an elevated temperature and conveniently at the reflux temperature of the solvent.
The compounds of formula (IV) may be prepared by reacting a compound of formula (V): 
wherein A, Ar and R1 are as defined in relation to the compound of formula (I), with a compound of formula (VI):
H2Nxe2x80x94COxe2x80x94Z1xe2x80x94L2xe2x80x83xe2x80x83(VI)
wherein Z1 is as defined in relation to the compound of formula (IV) and L2 represents a leaving group.
The reaction between the compounds of formulae (V) and (VI) is carried out in an aprotic solvent, such as acetonitrile, at a temperature which provides a suitable rate of formation of the required product, generally at an elevated temperature and conveniently at the reflux temperature of the solvent; preferably the reaction is carried out in the presence of base, usually an organic base such as a trialkylamine, for example triethylamine or a complex such as potassium fluoride on celite (Takashi Ando, Junko Yamawaki, Chemistry Letters, 1979, p.45).
A preferred leaving group L2 is a halogen atom, such as a chlorine atom.
The compounds of formula (V) are known, commercially available compounds.
The compounds of formula (VI) are known compounds or they are prepared using methods analogous to those used to prepare known, commercially available compounds.
In a further aspect the invention provides a process for the preparation of a compound of formula (I), which process comprises demethylating a compound of formula (VII): 
wherein A, Ar, R2, R3, R4 X and Z are as defined in relation to the compounds of formula (I); and thereafter, as required, converting any xe2x80x94NHxe2x80x94 moiety so formed into a group NR, wherein R represents C2-6 alkyl, an alkenyl or a cycloalkyl group.
The demethylation of the compounds of formula (VII) may be affected by using any conventional demethylation process, for example by use of methods disclosed in J. Org. Chem., 1975, 40, 1850, ibid, 1984, 49, 2081 or those methods disclosed in Synthesis 1991, 318.
The conversion of any xe2x80x94NHxe2x80x94 moiety into a group NR5 wherein R5 represents a C2-6 alkyl, an alkenyl or a cycloalkyl group may be carried out using conventional alkylation, alkenylation or cycloalkylation methods, by use of the appropriate alkylhalide, alkenylhalide or cycloalkylhalide, suitably an iodide, in the presence of a base such as potassium bicarbonate in an aprotic solvate such as tetrahrydrofuran.
In a further aspect the invention provides a compound of formula (VII) or a salt thereof or a solvate thereof as an intermediate.
A compound of formula (I), or a salt thereof, or a solvate thereof, may also be prepared by reacting a compound of formula (VIII): 
wherein R2, R3 R4 X and Z are as defined in relation to formula (I) and L3 is a leaving group, such as a halogen, with a compound of formula (IX): 
wherein A, Ar, R1 are as defined in relation to formula (I); and thereafter, if required, carrying out one or more of the following optional steps:
(i) converting a compound of formula (I) into a further compound of formula (I);
(ii) preparing a salt of the compound of formula (I) and/or a pharmaceutically acceptable solvate thereof.
The reaction between the compounds of formulae (VIII) and (IX) may be carried out in any suitable inert solvent, such as dichloromethane, in the presence of a base, usually an organic base, for example triethylamine, at a temperature which provides a suitable rate of formation of the required product, generally at an elevated temperature, such as the reflux temperature of the solvent.
A suitable value for L3 is chlorine.
A compound of formula (VIII) may be prepared by reaction between a compound of above defined formula (III) and a compound of formula (X):
H2Nxe2x80x94Zxe2x80x94L3xe2x80x83xe2x80x83(X)
wherein Z is as defined in relation to formula (I) and L3 is as defined in relation to formula (VII).
The reaction between the compounds of formulae (III) and (X) may be carried under conventional acylation conditions for example in an inert solvent, such as dichloromethane, in the presence of a base, usually an organic base, for example triethylamine, at a temperature which provides a suitable rate of formation of the required product, generally at a low to ambient temperature, preferably at ambient temperature.
The compounds of formula (X) are known, commercially available compounds.
A suitable conversion of one compound of formula (I) into a further compound of formula (I) involves the interconversion of variable R1 in the compounds of formula (I), for example the conversation of compounds wherein R1 is H into compounds of formula (I) wherein R1 represents alkyl, suitably C2-6 alkyl, alkenyl or cycloalkyl or the above mentioned conversation of compounds wherein R1 is methyl into compounds wherein R1 is hydrogen, C2-6 alkyl, alkenyl or cycloalkyl.
It will be appreciated that in any of the abovementioned reactions and conversions any reactive group in the substrate molecule may be protected, according to conventional chemical practice. The methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected.
As mentioned above the compounds of the invention are indicated as having useful therapeutic properties: The present invention accordingly provides a compound of formula (I), or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use as an active therapeutic substance.
More particularly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use in the treatment of and/or prophylaxis of arrhythmia, especially cardiac arrhythmia such as ventricular arrhythmia, and also ischaemic rhythm disorders.
A compound of formula (I), or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, may be administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier.
Accordingly, the present invention also provides a pharmaceutical composition comprising a compound of the general formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier therefor.
A compound of formula (I) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof is normally administered in unit dosage form.
An amount effective to treat the disorder hereinbefore described depends upon such factors as the efficacy of a compound of formula (I), the particular nature of the pharmaceutically acceptable salt or pharmaceutically acceptable solvate chosen, the nature and severity of the disorders being treated and the weight of the mammal. However, a unit dose will normally contain 0.1 to 500 mg for example 2 to 50 mg, of the compound of the invention. Unit doses will normally be administered once or more than once a day, for example 2,3,4,5 or 6 times a day, more usually 2 to 4 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 0.1 to 2500 mg, more usually 1 to 1000 mg, for example 1 to 200 mg, that is in the range of approximately 0.02 to 3 mg/kg/day, more usually 0.1 to 3 mg/kg/day, for example 0.15 to 2 mg/kg/day.
At the above described dosage range, no toxicological effects are indicated for the compounds of the invention.
In such treatment, the compound may be administered by any suitable route, e.g. by the oral, parenteral or topical routes. For such use, the compound will normally be employed in the form of a pharmaceutical composition in association with a human or veterinary pharmaceutical carrier, diluent and/or excipient, although the exact form of the composition will naturally depend on the mode of administration.
Compositions are prepared by admixture and are suitably adapted for oral, parenteral or topical administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, pastilles, reconstitutable powders, injectable and infusable solutions or suspensions, suppositories and transdermal devices. Orally administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use.
Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents. The tablets may be coated according to well known methods in the art.
Suitable fillers for use include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
Solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
For parenteral administration, fluid unit dose forms are prepared containing a compound of the present invention and a sterile vehicle. The compound, depending on the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the active compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum.
Parenteral suspensions are prepared in substantially the same manner except that the active compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the active compound.
For topical administration, the composition may be in the form of a transdermal ointment or patch for systemic delivery of the compound and may be prepared in a conventional manner, for example, as described in the standard textbooks such as xe2x80x98Dermatological Formulationsxe2x80x99xe2x80x94B. W. Barry (Drugs and the Pharmaceutical Sciencesxe2x80x94Dekker) or Harrys Cosmeticology (Leonard Hill Books).
In addition such compositions may contain further active agents such as anti-hypertensive agents and diuretics.
As is common practice, the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.
As used herein the term xe2x80x98pharmaceutically acceptablexe2x80x99 embraces compounds, compositions and ingredients for both human and veterinary use: for example the term xe2x80x98pharmaceutically acceptable saltxe2x80x99 embraces a veterinarily acceptable salt.
The present invention further provides a method for the treatment and/or prophylaxis of arrhythmia, especially cardiac arrhythmia such as ventricular arrhythmia, and also ischemic rhythm disorders in a human or non-human mammal which comprises administering an effective, non-toxic, amount of a compound of the general formula (I), or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof to a human or non-human marital in need thereof.
Conveniently, the active ingredient may be administered as a pharmaceutical composition hereinbefore defined, and this forms a particular aspect of the present invention.
In the treatment and/or prophylaxis of arrhythmia and/or ischaemic arrhythmia disorders the compound of the general formula (I), or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, may be taken in doses, such as those described above.
Similar dosage regimens are suitable for the treatment and/or prophylaxis of non-human mammals.
In a further aspect the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment of arrhythmia, especially cardiac arrhythmia such as ventricular arrhythmia, and also ischaemic rhythm disorders.
No toxicological effects are indicated when a compound of formula (I) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof is administered in the above mentioned dosage ranges.